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Liquid phase synthesis method for leuprorelin

A technology of leuprolide and liquid phase synthesis, applied in the field of liquid phase synthesis of leuprolide, can solve the problems of complicated operation, unsuitable for industrialized production and high product cost

Inactive Publication Date: 2019-04-09
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The Chinese published patent document CN106146622 adopts the strategy of different acid-base protecting groups. On the same resin, both acid-stabilized and alkali-stabilized protecting groups are used for total synthesis, which effectively avoids the generation of diketopiperazine, but the operation is extremely complicated. During the process, it is extremely unfriendly to the environment and is not suitable for industrial production
"Organic Chemistry" magazine, 2010, volume 30, No. 6, page 837-842, reports the method for synthesizing leuprolide by fragment method. The method adopts 2+7 fragment method. Although leuprolide is successfully synthesized, it uses The method of combining solid phase and liquid phase leads to high product cost, and toxic substances such as isobutyl chloroformate are used in liquid phase synthesis, which is not friendly to the environment
In order to solve the problem of reduced yield caused by diketopiperazine impurities, in order to obtain environmental friendliness and meet the needs of industrial production, this method is specially developed for industrial production

Method used

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  • Liquid phase synthesis method for leuprorelin
  • Liquid phase synthesis method for leuprorelin

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1, a kind of liquid phase synthesis method of leuprolide, described leuprolide Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt is under liquid phase conditions A novel magnetic catalyst Fe 3 O 4 The carboxyl protecting group R8 was removed under the action of @silica-α-chymotrypsin, and the new magnetic catalyst was separated from the product by electromagnet attraction, and then the pentapeptide and tetrapeptide fragment R6-D-Leu-Leu-Arg(R7)-Pro- NHEt is formed by condensation reaction and deprotection under the action of a condensing agent;

[0051] Where: R1 is BOC, Z, Fmoc or H;

[0052] R2 is BOC, Z, Bzl, Trt, Tos, Bom, Dnp or H;

[0053] R3 is BOC, For, H or Z;

[0054] R4 is Bzl, H, Tbu, Z, Boc or Tos;

[0055] R5 is Bzl, H, Tbu, 2,6-di-Cl-Bzl, Me, Z or 2-Cl-Z;

[0056] R8 is OME, OEt, Otbu, benzyl ester, thioester or organic salt, inorganic salt.

[0057] The condensation reaction between the carboxyl group and the amino group is completed through a...

Embodiment 2

[0058] Example 2, in the liquid phase synthesis method of leuprolide described in Example 1: the pentapeptide fragment R1-Pyr-His(R2)-Trp(R3)-Ser(R4)-Tyr(R5)- OR8 is synthesized by the following steps: firstly synthesize Tyr(R5)-OR8, and then react with R1-Ser(R4) protected by the α nitrogen end to generate R1-Ser(R4)-Tyr(R5)-OR8, which is deaminated and protected for later use ; NH protected by carboxyl R8 2 -Trp(R3)-OR8 reacts with α nitrogen-protected R1-His(R2) to generate R1-His(R2)-Trp(R3)-OR8, which is deprotected and reacts with α nitrogen-protected R1-Pyr Reaction to generate R1-Pyr-His(R2)-Trp(R3)-OR8, in the new magnetic catalyst Fe 3 O 4 The carboxyl protecting group R8 was removed under the action of @silica-α-chymotrypsin, and the magnetic catalyst was separated from the product by electromagnet attraction to obtain R1-Pyr-His(R2)-Trp(R3)-OH, which was combined with -Ser(R4 )-Tyr(R5)-OR8 undergoes condensation reaction to obtain R1-Pyr-His(R2)-Trp(R3)-Ser(R4)-...

Embodiment 3

[0059] Example 3, in the liquid phase synthesis method of leuprolide described in Example 1: the pentapeptide fragment R1-Pyr-His(R2)-Trp(R3)-Ser(R4)-Tyr(R5)- OR8 is synthesized by the following steps: firstly synthesize Tyr(R5)-OR8, then react with R1-Ser(R4) protected at the α nitrogen end to generate R1-Ser(R4)-Tyr(R5)-OR8, deprotect, and react with α The nitrogen-protected R1-Trp(R3) reacts to generate R1-Trp(R3)-Ser(R4)-Tyr(R5)-OR8, which is deprotected and reacted with the α nitrogen-protected R1-His(R2) to generate R1-His(R2)-Trp(R3)-Ser(R4)-Tyr(R5)-OR8, deprotected, reacted with α nitrogen-protected R1-Pyr to generate R1-Pyr-His(R2)-Trp( R3)-Ser(R4)-Tyr(R5)-OR8, in the new magnetic catalyst Fe 3 O 4 The carboxyl protecting group R8 was removed under the action of @silica-α-chymotrypsin, and the magnetic catalyst was separated from the product by electromagnet attraction to obtain a high-purity pentapeptide fragment R1-Pyr-His(R2)-Trp(R3)-Ser( R4)-Tyr(R5)-OH.

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Abstract

The invention relate to a liquid phase synthesis method for leuprorelin. The leuprorelin is prepared through condensation of a pentapeptide fragment Pyr-His-Trp-Ser-Tyr-OH and a tetrapeptide tetrapeptide D-Leu-Arg-Pro-NHEt under the condition of a liquid phase. The method adopts first amino acid carboxyl esterification, the saponification is avoided after a series of fragments are synthesized, a catalyst Fe3O4@silica-alpha-chymotrypsin is directly used for implementing the deprotection reaction, and a carboxyl fragment with high purity is efficiently synthesized. Then the carboxyl fragment andan amino fragment are subjected to condensation to obtain a full protection peptide, and a high-purity product is obtained after splitting and purifying. The method avoids the influence of a strong base in the saponification on the peptide, shortens the synthesis period, and avoids the severe reaction conditions in the traditional method, the catalyst is easy to recycle and use, in addition, theyield is high, the product purity is good, the purification is easy, the cost is low, the reaction condition is mild, and the liquid phase synthesis method is suitable for industrial production.

Description

technical field [0001] The present invention relates to a preparation method of a medicinal compound, in particular to a liquid phase synthesis method of leuprolide, which adopts a novel catalyst in the preparation process. Background technique [0002] Leuprolide is a gonadotropin-releasing hormone (GnRH) analog with the structural sequence: Pyr-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHEt. Its structural formula is as follows: [0003] [0004] At present, the methods for synthesizing leuprolide include solid-phase method, liquid-phase method and solid-liquid combination method. The solid-phase synthesis methods are mainly domestic patent reports, involving the strategic selection of different fully protected peptides, and then deprotection through different protective agent removal methods to obtain products. Chinese published patent document CN102464702B adopts acid-stable resin and Boc-protected amino acid strategy to synthesize fully-protected peptides. The fully-protec...

Claims

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Application Information

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IPC IPC(8): C07K7/23C07K1/06C07K1/02
CPCC07K7/23Y02P20/55Y02P20/584
Inventor 徐峰童梓权刘丽伏帅柳铎芳孙美禄
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD